Somatostatin (SS) is a neuropeptide which can act as a hormone, neuromodulator or an autocrine regulatory factor to inhibit secretion in a variety of endocrine, exocrine and neuronal target cells and, as a consequence, has been implicated in many physiological processes. The development of the stable SS analog (Sandostatin) currently employed for the detection and treatment of a variety of secretory tumors has also established the importance of this hormone in therapeutics and clinical diagnosis. SS acts to inhibit secretion via plasma membrane receptors which are coupled to one or more pertussis toxin sensitive G proteins. SS receptors activate multiple transduction pathways including inhibition of adenylyl cyclase and calcium channels and stimulation of potassium channels and phosphatases. A major breakthrough in the elucidation of SS action occurred in the last 5 months with reports describing the cloning of five distinct SS receptor cDNAs from human, mouse and rat brain libraries. These studies identified unique SS receptor subtypes with only about 45% identity in their amino acid sequences. Hydropathicity analysis of the primary structure of these SS receptors indicates that they contain 7-transmembrane alpha-helices and share significant sequence homology with other G protein coupled receptors, especially in the transmembrane domains. However, the functional properties of the cloned SS receptor subtypes remain to be determined, and the importance of the structural features suggested by analysis of sequence homologies are unknown. the PI's laboratory has already developed the tools and methods necessary to examine the biochemical and functional properties of SS receptors. The purpose of the present application is to provide short term salary support during a developmental leave to enable the PI to obtain first hand experience in recombinant DNA techniques and to initiate studies involving the cloning, expression and mutagenesis of SS receptors. The immediate objective is to expedite incorporation of the necessary molecular techniques into the PI's research program, so that they can be combined with the already available biochemical and signalling expertise with G- protein coupled receptors. In the long term these studies will (1) elucidate the functional properties which distinguish individual SS receptors and (2) identify the structural features which determine their specificity for both ligand binding and G protein coupling.